It is presently known that many human diseases are caused at least in part by proteins present in the cells of the afflicted individual. For example, certain proteins encoded by oncogenes are known to be responsible for the production of cancer in humans.
Included among these oncogenes is the oncogene designated as trk. The trk locus was originally identified by virtue of its activation as an oncogene in various human tumors (Martin-Zanca, D., et al. (1986). Nature, 319, 743-748). Subsequent studies revealed that the corresponding normal gene, the trk proto-oncogene, encodes a 790 amino acid-long cell surface receptor with intrinsic tyrosine protein kinase activity [(Martin-Zanca, D., et al. (1989). Mol. Cell. Biol., 9, 24-33)]. This protein, designated gp140.sup.trk, binds nerve growth factor (NGF) with high affinity, either by itself (Klein, R., et al. (1991). Cell, 65, 189-197) or in combination with a second NGF receptor, p75.sup.LNGFR (Hempstead, B. L., et al. (1991), Nature, 350, 678-683). Accumulative evidence indicates that gp.sub.140.sup.trk mediates the functional activity of NGF. NGF induces the rapid autophosphorylation of gp140.sup.trk on tyrosine residues, a step necessary to activate the receptor and to initiate the flow of signal transduction (Kaplan, D. R., et al. (1991). Nature, 350, 158-160; Kaplan, D. R., et al. (1991). Science, 252, 554-558; Klein, R., et al. (1991). Cell, 65, 189-197). Moreover, addition of NGF to NIH3T3 cells ectopically expressing gp140.sup.trk receptors induces the transient expression of c-Fos protein, DNA synthesis and morphologic transformation (Cordon-Cardo, C., et al. (1991). Cell, 66, 173-183). Similarly, addition of NGF to Xenopus oocytes microinjected with trk proto-oncogene mRNA induces germinal vesicle breakdown (Nebreda, A. R., et al. (1991). Science, 252, 558-561). Finally, transfection of NGF-unresponsive PC12 cells with a trk cDNA clone restores the ability of these mutant cells to respond to NGF (Loeb, D. M., et al. (1991). Cell, 66, 961-966).
Neoplasia is a process by which the controlling mechanisms that regulate cell growth and differentiation are impaired, resulting in progressive growth. During neoplasia, there is a characteristic failure to control cell turnover and growth. This lack of control causes a tumor to grow progressively, enlarging and occupying space in vital areas of the body. If the tumor invades surrounding tissue and is transported to distant sites, death of the individual often results.
The preferential killing of cancer cells while minimizing deleterious effects on normal cells is the desired goal in cancer therapy. In the past this has been accomplished using a variety of procedures. These procedures include the administration of chemicals (chemotherapy), radiation (radiotherapy), and surgery.
Recently there has been a rapid expansion of cancer treatments. Even though new treatments are being developed, the need still exists for improved methods for the treatment of most types of cancers.